Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitisation
Résumé
Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking estrogen receptor (ERα) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitising cells to tamoxifen may show utility in the clinic. To gain insight into how this might be achieved, we used chemical and genetic screens to identify targets and small molecule inhibitors that cause tamoxifen sensitisation. A high-throughput genetic screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 signalling pathway as a strong determinant of sensitivity to multiple ERα antagonists including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitisation, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.
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